On October 20, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the first presentation of results from an interim analysis of KEYNOTE-057, a Phase 2 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, for previously treated patients with high-risk non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) or CIS plus papillary disease (Cohort A) (Press release, Merck & Co, OCT 20, 2018, View Source [SID1234530005]). An interim analysis of the study’s primary endpoint showed a complete response (CR) rate of 38.8 percent (95% CI, 29.4-48.9) (n=103) at three months with KEYTRUDA in patients whose disease was unresponsive to Bacillus Calmette-Guérin (BCG) therapy, the current standard of care for this disease, and who were ineligible for or who refused to undergo radical cystectomy. These results, as well as other study findings, are being presented today in an oral session at the ESMO (Free ESMO Whitepaper) 2018 Congress (Abstract #864O).

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"Treatment options for high-risk non-muscle invasive bladder cancer have historically been limited, with many patients relying on surgery as their only option following disease recurrence. Additionally, about 40 percent of patients with high-risk non-muscle invasive bladder cancer progress to muscle invasive disease," said professor Ronald de Wit, M.D., Ph.D., group leader experimental systemic therapy of urogenital cancers, Erasmus MC Cancer Institute. "These data from KEYNOTE-057 are encouraging for patients with this hard-to-treat form of bladder cancer who are ineligible for surgery."

"The nearly 40 percent complete response rate with KEYTRUDA in patients with high-risk non-muscle invasive bladder cancer is encouraging and adds to the growing body of data showing the anti-tumor activity of KEYTRUDA as monotherapy across different types of cancer," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "There are few options for the treatment of recurrent non-muscle invasive bladder cancer, and we look forward to continuing to study KEYTRUDA for the treatment of these patients whose disease has reoccurred and who have limited therapeutic options."

Additional Data from KEYNOTE-057 (Abstract #864O)

KEYNOTE-057 is a Phase 2, single-arm, multi-cohort study evaluating KEYTRUDA as monotherapy in patients with high-risk NMIBC that has not responded to treatment with BCG therapy and who are ineligible for or who have refused to undergo radical cystectomy. The study’s primary endpoints are CR rate (Cohort A only) and disease-free survival rate (Cohort B only). The secondary endpoints include safety and duration of response.

Data presented at ESMO (Free ESMO Whitepaper) are from an interim analysis of patients with CIS or CIS plus papillary disease (Cohort A) (n=103). Findings showed a CR rate of 38.8 percent (95% CI, 29.4-48.9) (n=40/103) at three months. The non-CR rate was 55.3 percent (95% CI, 45.2-65.1) (n=57/103) at three months, and patients had either persistent disease (CIS +/- papillary tumor), NMIBC stage progression (CIS +/- high-grade Ta at baseline to T1 disease) or extravesical disease. At the time of analysis, 72.5 percent of responding patients had an ongoing response (n=29/40) and 25 percent experienced recurrent disease after CR (n=10/40). One patient who did not develop recurrent disease discontinued study treatment and started alternative therapy. No patients in Cohort A developed muscle invasive or metastatic urothelial carcinoma. Of the patients who achieved a CR at three months, 80 percent had a CR lasting for six months or longer, based on the Kaplan-Meier method. The median duration of response was not yet reached (range, 0+ to 14.1+). The median follow-up was 14.0 months (range, 4.0-26.3 months).

The safety of KEYTRUDA in KEYNOTE-057 was consistent with what has been seen in previous trials among patients treated with KEYTRUDA monotherapy. Treatment-related adverse events (TRAEs) occurred in 63.1 percent of patients. The most common TRAEs with an incidence of 5 percent or more were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%) and maculopapular rash (5.8%). Grade 3-5 TRAEs occurred in 13 patients (12.6%), and there was one treatment-related death, per investigator assessment.

Additional Information About KEYNOTE-057

The target enrollment for KEYNOTE-057 (ClinicalTrials.gov, NCT02625961) is 260 patients across two cohorts: patients with CIS or CIS plus papillary disease (Cohort A) (n=130) and patients with papillary disease without CIS (Cohort B) (n=130). Patients in both cohorts receive KEYTRUDA (200 mg fixed dose intravenously every three weeks) until recurrence, disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In this study, BCG-unresponsive high-risk NMIBC is defined as persistent or recurrent disease despite adequate BCG therapy or stage progression despite adequate BCG induction therapy. Patients were considered high risk if their tumors were classified as T1, high-grade Ta and/or CIS based on the American Joint Committee on Cancer (AJCC) TNM system.

About Bladder Cancer

Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Bladder cancers are described based on how far they have invaded into the wall of the bladder. Non-muscle invasive bladder cancer occurs when the cancer has not grown into the main muscle layer of the bladder. Eighty percent of bladder cancer patients are diagnosed with NMIBC. Worldwide, bladder cancer is the tenth most common cancer and the thirteenth most common cause of cancer death. It is estimated that almost 550,000 new cases of bladder cancer will be diagnosed in 2018.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 850 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALKgenomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1 fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

On October 20, 2018 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX) (TASE: BLRX.TA), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported its additional data from the in-depth analyses of biopsies of the dual combination arm of the Phase 2a COMBAT/KEYNOTE-202 study, evaluating patients with metastatic pancreatic adenocarcinoma (PDAC) treated with BL-8040 in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside of the United States and Canada) (Press release, BioLineRx, OCT 20, 2018, View Source;p=RssLanding&cat=news&id=2372552 [SID1234530001]). The results presented today at a poster discussion session at the European Society for Medical Oncology 2018 Congress, in Munich, Germany, demonstrate that BL-8040 significantly improves T-cell infiltration into the tumor and reduces immunosuppression in the tumor microenvironment. These data follow top-line results of the COMBAT/KEYNOTE-202 study announced yesterday, October 19, 2018, showing encouraging disease control and extended overall survival, particularly in patients undergoing second-line treatment.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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The study included 37 patients with metastatic PDAC who had disease progression after one or more previous lines of treatment. Study treatment consisted of an initial 5-day priming period of BL-8040 monotherapy, followed by repeated 3-week cycles of BL-8040 in combination with KEYTRUDA. In addition to clinical efficacy assessments, the study included a number of pharmacodynamic assessments to support BL-8040’s mechanism of action as an immuno-oncology agent.

The additional data from in-depth analyses of biopsies taken at screening and following monotherapy or combination treatment of BL-8040 and KEYTRUDA demonstrate that in 75% of the available biopsies, BL-8040 treatment promotes an increase in the number of infiltrating CD4+, CD8+ and CD8+Granzyme B+ cytotoxic T-cells. The greatest improvement in T-cell infiltration was observed following combination treatment of BL-8040 and KEYTRUDA and was correlated with stable disease for 8 cycles of treatment. Furthermore, increased infiltration of activated CD4 and CD8 T-cells was accompanied by a pronounced decrease in the number of tumor cells, as well as by a decrease in myeloid-derived suppressor cells, a cell type known to impede the anti-tumor immune response.

Philip Serlin, Chief Executive Officer of BioLineRx, commented. "The data we disclosed today further support BL-8040 as a powerful immune modulating agent, which promotes infiltration of T-cells into the tumor and decreases immuno-suppressive cells in the tumor microenvironment, even more so when combined with KEYTRUDA. This, once again, attests to the potential of the combination treatment as an effective immunotherapy for pancreatic cancer. We look forward to commencing the triple combination arm through the addition of chemotherapy expected by the end of this year, with results expected in the second half of 2019."

About the COMBAT/KEYNOTE-202 Study

The Phase 2a COMBAT/KEYNOTE-202 study is currently an open-label, multicenter, single-arm trial designed to evaluate the safety and efficacy of the combination of BL-8040 and KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study is primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies, and is being carried out in the US, Israel and additional territories. The study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary, to support a Phase 2a program investigating BioLineRx’s BL-8040 in combination with KEYTRUDA in patients with metastatic pancreatic cancer.

In July 2018, the Company announced the expansion of its immuno-oncology collaboration with MSD to include a triple combination arm investigating the safety, tolerability and efficacy of BL-8040, KEYTRUDA and chemotherapy. The triple combination arm will focus on second-line pancreatic cancer patients. Thirty to fifty patients will be enrolled in this arm, planned for initiation in the fourth quarter of 2018.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells to peripheral blood and to be effective at inducing direct tumor cell death. In addition, clinical findings have demonstrated the ability of BL-8040 to mediate infiltration of T-cells into tumors that were previously immunologically "cold" and devoid of immune cell infiltrate. Immune checkpoint inhibitors (such as KEYTRUDA) produce anti-cancer effects by increasing the activity of T-cells through blockade of the interaction between the immune checkpoint receptor PD-1, on T-cells, and its ligand PD-L1, on tumor cells. Pancreatic cancers have very little T-cell infiltrate, making them less susceptive to checkpoint blockade than other tumors that are infiltrated by T-cells. Therefore, combining BL-8040 with immune checkpoint blockade is predicted to increase the responsiveness of pancreatic cancer patients to immunotherapy. Further increase in the sensitivity of pancreatic cancer cells to BL-8040 and KEYTRUDA may be achieved by chemotherapy-mediated immunogenic cell death and exposure of new tumor antigens, resulting in activation of new anti-cancer T cell clones.

About BL-8040

BL-8040 is a short synthetic peptide for the treatment of hematological malignancies, solid tumors, and stem cell mobilization. It functions as a high-affinity best-in-class antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells and immune-cells, sensitization of cancer cells to chemo- and bio-based anti-cancer therapies, and direct anti-cancer effect by inducing programmed cell death (apoptosis). BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

On October 20, 2018 Novartis reported positive results from the global Phase III SOLAR-1 trial evaluating the investigational alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant (Press release, Novartis, OCT 20, 2018, View Source [SID1234529998]). The trial evaluated the efficacy and safety of alpelisib in postmenopausal women with PIK3CA mutated hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer that progressed on or after an aromatase inhibitor with or without a CDK4/6 inhibitor. These data will be presented today at the official press briefing at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress and as a late-breaker during the Presidential Symposium (Abstract LBA3_PR).

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In patients with PIK3CA mutated HR+/HER2- advanced breast cancer, BYL719 plus fulvestrant demonstrated a median progression-free survival (PFS) of 11 months (95% CI: 7.5-14.5 months) compared to 5.7 months (95% CI: 3.7-7.4 months) for fulvestrant alone. BYL719 plus fulvestrant reduced the risk of death or progression in those patients by an estimated 35% compared to fulvestrant alone (HR=0.65; 95% CI: 0.50-0.85; p<0.001). Overall response rate (ORR), indicating a reduction in tumor size of at least 30%, was more than doubled in patients with measurable disease who received BYL719 plus fulvestrant (36%) compared to those receiving fulvestrant alone (16%)[1].

"The results from SOLAR-1 are the most encouraging observed to date from a trial evaluating a PI3K inhibitor for patients with PIK3CA mutated HR+/HER2- advanced breast cancer," said Fabrice André, MD, PhD, research director and head of INSERM Unit U981, and professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. "These data have the potential to allow physicians to address an unmet need in this patient population by using a biomarker-driven treatment to inform their sequencing decisions."

PFS treatment effect was consistent across all subgroups, and regardless of whether aromatase inhibitor treatment was given, with or without a CDK4/6 inhibitor. The significant PFS improvement demonstrated with BYL719 plus fulvestrant in patients with a PIK3CA mutation was not observed for patients without the mutation[1].

"We are excited about the meaningful results seen in SOLAR-1 and about the possibility to reimagine what potential treatment options could look like for patients living with PIK3CA mutated HR+/HER2- advanced breast cancer – some of who were previously treated with a CDK4/6 inhibitor," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We are actively engaging in discussions on these results with health authorities worldwide."

Most adverse events were mild to moderate in severity and generally manageable through dose modifications and medical management. The discontinuation rate of BYL719 plus fulvestrant due to adverse events was 5% compared to 1% for fulvestrant alone. The most common all-grade adverse events (>=30%) were hyperglycemia (64% vs 10%), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 11%) and rash (36% vs. 6%). Of these, the most common grade 3/4 events (>=5%) were hyperglycemia (37% vs. <1%), rash (10% vs. <1%), and diarrhea (7% vs. <1%)[1].

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival. Further analysis from SOLAR-1 will be presented and discussed at future medical congresses.

About PI3K inhibition in advanced breast cancer
Studies have established the role of PI3K signaling in several processes for cancer progression, including cell metabolism, growth, survival and motility[3]. Activation of the PI3K pathway in breast cancer is associated with resistance to endocrine therapy, disease progression and poorer prognosis[4],[5].

Proteins in the PI3K pathway consist of four smaller parts called isoforms[6]. Approximately 40% of HR+ advanced breast cancer patients have genetic mutations that activate the alpha isoform, called PIK3CA mutations[2]. Mutations in the three other isoforms are typically not associated with advanced breast cancer[6].

Currently, there are no approved PI3K inhibitors for breast cancer.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with the PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[7].

On October 20, 2018 TESARO, Inc. (NASDAQ: TSRO), an oncology-focused biopharmaceutical company, today summarized updated Phase 1 GARNET data of TSR-042 (anti-PD-1 antibody) in patients with recurrent or advanced microsatellite instability high (MSI-H) endometrial cancer presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, TESARO, OCT 20, 2018, View Source [SID1234529996]). Blinded, pooled interim safety data from the Phase 3 PRIMA trial of niraparib in patients with first-line ovarian cancer regardless of biomarker status were also presented in a poster discussion session and additional data from the QUADRA trial of niraparib for treatment of late-line ovarian cancer beyond BRCAmut were presented in a poster display.

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"The updated results from GARNET presented at ESMO (Free ESMO Whitepaper) demonstrate robust clinical activity of TSR-042 in patients with MSI-H endometrial tumors," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "In addition, blinded, pooled interim safety data from the ongoing PRIMA study of niraparib as maintenance therapy in first line ovarian cancer demonstrated a favorable tolerability profile for niraparib when dosed according to a patient’s weight and platelet count compared to a fixed starting dose. These prospective data confirmed that adverse events are reduced for patients starting niraparib at an individualized dose, including a reduction in symptomatic events that are particularly meaningful to patients. We look forward to announcing top-line results for the PRIMA study in late 2019."

TSR-042 (anti-PD-1 antibody)

GARNET: Efficacy data indicates robust activity of TSR-042 in patients with MSI-high endometrial cancer
GARNET is a multicenter, open-label, Phase 1 dose-escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. The weight-based dose escalation and fixed-dose safety portions of the GARNET study have been completed. The ongoing cohort expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks (Q3W) for the first 4 cycles, and 1000 milligrams every 6 weeks (Q6W) thereafter in four cohorts: MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer and non-small cell lung cancer (NSCLC). Data presented at ESMO (Free ESMO Whitepaper) included safety and efficacy data from the cohort of patients with MSI-H endometrial cancer.

At the time of data cutoff, 35 patients with MSI-H endometrial cancer had received treatment with TSR-042. Among the 25 patients with MSI-H endometrial cancer who had at least one post-baseline tumor assessment, one had a complete response and 12 had partial responses (including 1 unconfirmed response) by immune related RECIST (irRECIST) criteria (ORR 52%). Twelve of the 13 responses are ongoing (92%), including three patients with partial responses who have thus far received over 60 weeks of treatment with TSR-042. Three additional patients (12%) had stable disease. Median duration of response was not reached.

Preliminary safety findings among the 35 MSI-H endometrial patients indicate TSR-042 is generally well-tolerated. Grade ≥3 treatment-related treatment-emergent adverse events (TEAEs) were reported in 4 out of 35 patients (11.4%).

The data support the unique and convenient dose of TSR-042 of 500 mg Q3W for the first 4 doses, then 1000 mg Q6W thereafter. At this dose, TSR-042 maintained serum concentrations required to retain maximum receptor occupancy throughout the dosing cycle.

The GARNET study is intended to support a Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) in 2019.

ZEJULA (niraparib)

PRIMA: Prospective validation of individualized niraparib dose regimen based on patient baseline body weight & platelet counts; Rates of adverse events in blinded, pooled patient groups decreased with individualized starting dose compared to fixed starting dose
PRIMA is a double-blind, randomized Phase 3 study designed to evaluate niraparib versus placebo as maintenance therapy in first-line ovarian cancer patients. Platinum responsive patients were initially randomized 2:1 to start niraparib at 300 mg once-daily or placebo and the protocol was subsequently amended to require an individualized starting dose of 200 mg once-daily in patients with baseline weight <77kg or platelet count <150K/μL and 300 mg in all other patients. The trial remains blinded for efficacy and safety.

Among the 727 patients dosed on the study, 480 patients were treated with a fixed 300 mg starting dose of niraparib or placebo and 247 patients were treated with an individualized dose of 300 mg or 200 mg of niraparib based on weight and platelet count or placebo. The findings presented were from evaluable patients with ≥30 days of safety data from blinded pooled niraparib and placebo and indicate improved tolerability with niraparib at the individualized starting dose. TEAEs grade ≥ 3 were lower (36%) in the individualized dosing group (pooled niraparib and placebo) as compared with the group that received a fixed starting dose of 300 mg of niraparib or placebo (52.7%). There were fewer dose reductions and dose discontinuations in patients treated with the individualized starting dose compared with the fixed starting dose. TEAEs leading to treatment discontinuation remained low for both groups at 7.9% for the fixed starting dose and 5.3% for the individualized starting dose group.

The rates of hematologic toxicities of all grades, including grade ≥ 3, were lower with introduction of an individualized starting dose. Grade ≥3 non-hematologic toxicities (nausea, vomiting, fatigue, hypertension, and insomnia) decreased with an individualized starting dose.

QUADRA: Clinical benefit of niraparib treatment demonstrated in late-line ovarian cancer setting, including patients with platinum resistant and refractory disease
Late line ovarian cancer represents a high unmet medical need and efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. Previous studies have shown meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer only in populations with BRCA mutations. QUADRA, a single arm study, was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or later treatment of patients with ovarian cancer, regardless of platinum sensitivity or biomarker status.

Niraparib treatment demonstrated durable clinical activity in late-line (≥ 4th line) patients with BRCAmut tumors, with an ORR of approximately 30%, including patients with platinum-sensitive, -resistant, and -refractory disease, and a median duration of response of 9.2 months. The clinical benefit rate (CBR; CR+PR+SD) at 16 weeks and 24 weeks were 56% and 38%, respectively. A gradient of clinical activity based on platinum sensitivity was demonstrated in the BRCAmut patient population, with greatest activity demonstrated in patients with platinum-sensitive disease (ORR 39%), mOS was not reached (95% CI 19, NE). However, even patients with platinum-resistant and platinum-refractory disease experienced benefit from niraparib treatment with ORR of 33% and 19%, and mOS of 26.0 and 23.3 months, respectively.

Clinical benefit of niraparib extended beyond patients with BRCA mutations in this late-line setting. Patients with non-BRCAmut/HRDpos platinum-sensitive disease had an ORR of 20%. In total, the biomarker-driven population (BRCAmut regardless of platinum status and non-BRCAmut HRDpos platinum-sensitive patients) included 98 patients with ORR of 26%, mDOR of 8.3 months, and a mOS of 23.3 months.

The safety profile in the QUADRA treatment study was consistent with the safety profile observed in the NOVA maintenance population.

Details of TESARO’s poster presentations are as follows (all times local):

ZEJULA (niraparib)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:59 AM

A prospective evaluation of tolerability of niraparib dosing based upon baseline body weight (wt) and platelet (plt) count: Blinded pooled interim safety data from the PRIMA Study

Poster Discussion, Abstract: 941PD, Location: ICM – Room 13, Poster Displayed: Hall B4

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset

Poster Session, Abstract: 944P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

OVARIO: A single-arm, open-label phase 2 study of maintenance therapy with niraparib + bevacizumab in patients with advanced ovarian cancer after response to frontline platinum-based chemotherapy

Poster Session, Abstract: 999TiP, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Real world occurrence of top three clinical-trial reported adverse events of PARP inhibitor niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer, a national retrospective observational study of a 200 mg/day starting-dose cohort

Poster Session, Abstract: 986P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Brain metastases in primary ovarian cancer: real-world data

Poster Session, Abstract: 946P, Location: Hall A3

TSR-042 (anti-PD-1)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:15 AM

Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H endometrial cancer

Poster Discussion, Abstract: 935PD, Location: ICM – Room 13, Poster displayed: Hall B4

Niraparib is marketed in the United States and Europe under trade name ZEJULA.

About ZEJULA (Niraparib)
ZEJULA (niraparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated in the United States and in the EU for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect. Important Safety Information Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients.
ZEJULA can cause fetal harm and females of reproductive potential should use effective contraception.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%). Please see full U.S. prescribing information, including additional important safety information, available at www.zejula.com.

About GARNET
The ongoing Phase I GARNET trial is evaluating TSR-042 as monotherapy in patients with advanced solid tumors. GARNET included a weight-based dose escalation study (Part 1) and a fixed-dose safety study (Part 2A), both of which have been completed. Results of these studies were used to determine the recommended Phase 2 dose (RP2D; 500 mg Q3W for the first 4 cycles then 1000 mg Q6W). The study is now enrolling patients with MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer, and NSCLC into four large expansion cohorts.

About TSR-042

TSR-042 is an investigational humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. TSR-042 is the only anti-PD-1 therapy administered as monotherapy every 3 weeks for 4 doses then every 6 weeks thereafter. TSR-042 was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).

More than 60 Late Breaking Abstracts (LBA’s) are scheduled to be published at this year’s European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (E.S.M.O 2018). Below you will find the 13 published on Friday 19th October, the first day of the conference. For full analysis identifying new technologies, drugs, targets, start-ups etc. we recommend Commercial Interest at E.S.M.O Annual Meeting 2018: Analytical Tool.

• LBA12_PR – PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Cost effectiveness analysis results
• LBA28 – Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions
• LBA29 – CARRIE: A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Istiratumab (MM-141) plus Nab-Paclitaxel and Gemcitabine versus Nab-Paclitaxel and Gemcitabine in Front-line Metastatic Pancreatic Cancer
• LBA30 – ERA 223: A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC)
• LBA50 – Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study
• LBA51 – Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study
• LBA57 – Overall survival results of ceritinib in ALKi-naïve patients with ALK-rearranged NSCLC (ASCEND-3)
• LBA58 – Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ) in the phase 3 ALTA-1L trial
• LBA59 – Primary efficacy and updated safety of ceritinib (450 mg or 600 mg) with food vs 750 mg fasted in ALK+ metastatic NSCLC ASCEND-8)
• LBA60 – Uncommon EGFR mutations in lung adenocarcinomas: clinical features and response to tyrosine kinase inhibitors
• LBA61 – Phase II results for single-agent nazartinib (EGF816) in adult patients (pts) with treatment-naive EGFR-mutant non-small cell lung cancer (NSCLC)
• LBA66 – A phase II/III trial of hafnium oxide nanoparticles activated by radiotherapy in the treatment of locally advance soft tissue sarcoma of the extremity and trunk wall
• LBA67 – Cabozantinib in Patients With Advanced Osteosarcomas and Ewing sarcomas: a French Sarcoma Group (FSG)/ US National Cancer Institute phase II collaborative study.

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